Exploring the causes of cancer metastasis Evidence suggests that the progression of breast cancer depends on interactions between cancer cells and the surrounding microenvironment. Researchers in the BONEMETTNC project aim to dissect the role of the microenvironment in breast cancer metastasis, work which could open up new therapeutic avenues, as Dr Thordur Oskarsson explains The most common
form of cancer in women, accounting for around 25 percent of all female cases across the world, breast cancer causes more than 500,000 deaths a year. The vast majority of these deaths are caused by metastasis, the process by which malignant cells spread to distant organs, a topic that lies at the core of the BONEMETTNC project. “We are trying to dissect the role of the surrounding microenvironment in breast cancer metastasis,” says Dr Thordur Oskarsson, the project’s Principal Investigator. The consequences of mutations and other changes in cancer cells are frequently context-dependent, underlining the importance of research into the surrounding microenvironment, or metastatic niche, which supports the continued growth of the cancer. “Over the last few years we have focused in particular on the extracellular matrix, which is the non-cellular component of the microenvironment,” outlines Dr Oskarsson.
Extracellular matrix The extracellular matrix fills the space between cells within tissues and performs a number of key functions, including providing structural support and regulating cellular communication. In cancer, the extracellular matrix is distinct from healthy tissue and resembles the matrix that is produced during wound healing. The development of a cancer
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associated matrix is a complex process, however it is recognized that reactive stromal fibroblasts, a type of connective tissue cell, play a prominent role in matrix production and maturation. This is an area of great interest to Dr Oskarsson. “We aim to dissect the molecular cross-talk between these stromal cells and cancer cells,” he says. These interactions are highly dynamic and the resulting extracellular matrix niche may not form instantaneously. Therefore, when disseminated cancer cells arrive at a distant site, the microenvironment may not be welcoming, leading to the elimination of most of the cancer cells. The continuous cross-talk
fluids of breast cancer patients. These are patients with systemic metastasis, so we think that these samples may provide a window to look at the most aggressive cancer cells in metastasis,” says Dr Oskarsson. One of the reasons that Dr Oskarsson is interested in molecules like TNC and other matricellular proteins is that while they do not contribute significantly to the scaffolding structure of the extracellular matrix, they are important for cell regulation and the modulation of signalling pathways. “They can determine cell fate, particularly under stress, and we think that this is very important for the metastatic colonisation,” he outlines.
Stem cell properties are likely to be important for the maintenance and progression of breast cancer between cancer cells and stroma induces changes in the microenvironment, which may generate a supportive niche that promotes cancer growth. “Moreover, we have observed that the cancer cells that can bring their own niche components have a selective advantage in secondary organs,” explains Dr Oskarsson. The extracellular matrix protein tenascin C (TNC), a type of matricellular protein, is an essential component of the metastatic niche in breast cancer. “We’ve observed that TNC is expressed in cancer cells that we isolated from the pleural
A second major reason for studying TNC and other matricellular proteins is their expression in the normal stem cell niches of a number of different tissues. This could indicate that TNC plays a role in regulating the properties of normal stem cells, properties which have increasingly been shown to be important in the development and progression of cancer. “In a tumour, stem cell attributes, such as self-renewal and the ability to resist stress, have essentially been hi-jacked by the cancer cells, and during metastatic progression, cancer cells express their
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